Dynamics of diffusive cell signaling relays

Abstract

Cells can communicate with each other by emitting diffusible signaling molecules into the surrounding environment. However, simple diffusion is slow. Even small molecules take hours to diffuse millimeters away from their source, making it difficult for thousands of cells to coordinate their activity over millimeters, as happens routinely during development and immune response. Moreover, simple diffusion creates shallow, Gaussian-tailed concentration profiles. Attempting to move up or down such shallow gradients -to chemotax -is a difficult task for cells, as they see only small spatial and temporal concentration changes. Here, we demonstrate that cells utilizing diffusive relays, in which the presence of one type of diffusible signaling molecule triggers participation in the emission of the same type of molecule, can propagate fast-traveling diffusive waves that give rise to steep chemical gradients. Our methods are general and capture the effects of dimensionality, cell density, signaling molecule degradation, pulsed emission, and cellular chemotaxis on the diffusive wave dynamics. We show that system dimensionality -the size and shape of the extracellular medium and the distribution of the cells within it -can have a particularly dramatic effect on wave initiation and asymptotic propagation, and that these dynamics are insensitive to the details of cellular activation. As an example, we show that neutrophil swarming experiments exhibit dynamical signatures consistent with the proposed signaling motif. Interpreted in the context of these experiments, our results provide insight into the utility of signaling relays in immune response.

Long-range morphogen gradient formation by cell-to-cell signal propagation

“…For even larger feedback strengths, the gradient decay length decreases again, see figure 3, and profiles become rather flat with a high base level of morphogen due to the positive feedback and a shallow spatial profile, see figures D1, D2 in the appendix. We speculate that in this regime, the signaling relay may lead to traveling fronts, similar to those reported in [49]. Overall, our results demonstrate that the formation of steady-state gradients is indeed possible in systems incorporating a signaling relay and that the gradient decay length depends on the feedback strength.…”

Emergence of synchronized multicellular mechanosensing from spatiotemporal integration of heterogeneous single-cell information transfer

“…Although both mechanisms could contribute to the information flow within the multicellular network, we suggest gap-junction and contact-dependent signaling as the dominant mechanism (Figure 3B versus Figures 3C or S5). Although a recent study suggested that positive feedback of a diffusive signaling mechanism can drive accelerated, long-range information transmission (Dieterle et al, 2019), the external flow in our system is likely to rapidly dilute the diffusive messenger (Gregor et al, 2010). The contact-dependent information flow hypothesis is also supported by our previous studies where we demonstrated that blocking gap junctions or inserting weakly communicating cells impaired the information flow (Potter et al, 2016;Sun et al, 2012).…”

Emergence of synchronized multicellular mechanosensing from spatiotemporal integration of heterogeneous single-cell information transfer

“…While both mechanisms could contribute to the information flow within the multicellular network, we suggest contact-dependent signaling as the dominant mechanism. While a recent study suggested that positive feedback of a diffusive signaling mechanism can drive accelerated, long-range information transmission 53 , the external flow in our system is likely to rapidly dilute the diffusive messenger 54 . The contact-dependent information flow hypothesis is also supported by our previous studies where we demonstrated that blocking gap junctions, or inserting weakly communicating cells impared the information flow 14,15 .…”